10-46010437-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001145263.2(NCOA4):c.1484C>T(p.Ser495Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,614,176 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (23 hom.)
• Consequence: NCOA4 NM_001145263.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.32

Genes affected

NCOA4 (HGNC:7671): (nuclear receptor coactivator 4) This gene encodes an androgen receptor coactivator. The encoded protein interacts with the androgen receptor in a ligand-dependent manner to enhance its transcriptional activity. Chromosomal translocations between this gene and the ret tyrosine kinase gene, also located on chromosome 10, have been associated with papillary thyroid carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes are present on chromosomes 4, 5, 10, and 14. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014239132).
• BP6: Variant 10-46010437-G-A is Benign according to our data. Variant chr10-46010437-G-A is described in ClinVar as [Benign]. Clinvar id is 715257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00226 (344/152298) while in subpopulation EAS AF= 0.0189 (98/5184). AF 95% confidence interval is 0.0159. There are 3 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA4	NM_001145263.2	c.1484C>T	p.Ser495Leu	missense_variant	8/10	ENST00000581486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA4	ENST00000581486.6	c.1484C>T	p.Ser495Leu	missense_variant	8/10	1	NM_001145263.2	P2

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00451 AC: 1132 AN: 251246 Hom.: 8 AF XY: 0.00415 AC XY: 564 AN XY: 135876

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.0186

Gnomad SAS exome AF: 0.00630

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00227 AC: 3319 AN: 1461878 Hom.: 23 Cov.: 32 AF XY: 0.00234 AC XY: 1705 AN XY: 727236

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.00551

Gnomad4 EAS exome AF: 0.0134

Gnomad4 SAS exome AF: 0.00639

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00429

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74470

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.00828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00286

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;.;.;.
MetaRNN	Benign	0.014	T;T;T;T;T;T;T
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Vest4		0.38
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142672975; hg19: chr10-51585385;